U.S. patent number 5,214,156 [Application Number 07/866,391] was granted by the patent office on 1993-05-25 for therapeutically useful tetralin derivatives.
This patent grant is currently assigned to The Upjohn Company. Invention is credited to Bengt R. Andersson, Per Arvid E. Carlsson, Kjell A. I. Svensson, Hakan V. Wikstrom.
United States Patent |
5,214,156 |
Andersson , et al. |
May 25, 1993 |
Therapeutically useful tetralin derivatives
Abstract
This invention is therapeutically useful tetralins and
pharmaceutically acceptable acid addition salts thereof of the
formula ##STR1## wherein YR.sub.1 is OR.sub.1 at the 8 position
where R.sub.1 is --CH.sub.2 --(C.sub.3-8 cycloalkyl); R.sub.2 is
hydrogen or C.sub.1-3 alkyl; R.sub.3 is --CH.sub.2 --(C.sub.3-8
cycloalkyl); R.sub.4 is hydrogen, C.sub.1-8 alkyl, --CH.sub.2
--(C.sub.3-4 cycloalkyl), --(CH.sub.2).sub.m --R.sub.5 or
--CH.sub.2 --CH.sub.2 --X--(CH.sub.2).sub.n CH.sub.3 ; n is zero to
3 and m is 2 or 3; X is oxygen or sulfur; R.sub.5 is phenyl,
C.sub.1-3 alkoxy, C.sub.1-3 alkyl, 2-thiophene, 3-thiophene, or
phenyl substituted with one or two substituent groups selected from
chlorine, bromine or fluorine; and with the proviso that when
R.sub.3 contains more than four carbon atoms and R.sub.4 is alkyl,
said alkyl contains from 1 to 3 carbon atoms. Alternatively,
--YR.sub.1 is --S--(C.sub.1-3 alkyl) at the 5, 6, 7 or 8 position
of the aromatic ring or OR.sub.1 at the 8 position where R.sub.1 is
selected from the group consisting of C.sub.1-8 alkyl, C.sub.2-8
alkenyl, --CH.sub.2 --(C.sub.3-8 cycloalkyl) or benzyl; R.sub.2 is
hydrogen or (C.sub.1 -C.sub.3) alkyl; R.sub.3 is --CH.sub.2
--(C.sub.3 -C.sub.8) cycloalkyl; R.sub.4 is --(CH.sub.2).sub.m
--(2-thiophenyl or 3-thiophenyl); and m is 2 or 3.
Inventors: |
Andersson; Bengt R. (Lindome,
SE), Carlsson; Per Arvid E. (Goteborg, SE),
Svensson; Kjell A. I. (Alingas, SE), Wikstrom; Hakan
V. (Partille, SE) |
Assignee: |
The Upjohn Company (Kalamazoo,
MI)
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Family
ID: |
27497040 |
Appl.
No.: |
07/866,391 |
Filed: |
April 10, 1992 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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784609 |
Oct 29, 1991 |
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571561 |
Aug 30, 1990 |
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173130 |
Mar 25, 1988 |
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Current U.S.
Class: |
549/75; 564/374;
564/382; 564/428 |
Current CPC
Class: |
C07C
217/74 (20130101); C07C 323/38 (20130101); C07D
333/20 (20130101); C07C 2602/10 (20170501) |
Current International
Class: |
C07C
217/00 (20060101); C07C 217/74 (20060101); C07C
323/00 (20060101); C07C 323/38 (20060101); C07D
333/00 (20060101); C07D 333/20 (20060101); C07P
333/20 (); A61K 031/38 (); A61K 031/135 (); C07C
211/00 () |
Field of
Search: |
;514/654,657,438
;564/374,382,428 ;549/75 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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0168505 |
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Jan 1986 |
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EP |
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0272534 |
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Jun 1988 |
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EP |
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1377356 |
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Dec 1974 |
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JP |
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1597140 |
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Sep 1981 |
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GB |
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Other References
Wikstrom, H. et al., "Conformational Analysis of 2-Aminoindans and
2-(Aminomethyl)indans in Relation to Their Central Dopaminergic
Effects and a Dynamic Dopamine Receptor Concept," J. Med. Chem.
30(7):1115-20 (1987). .
Cannon, J. G. et al., "Conformationally Restricted Congeners of
Dopamine Derived from 2-Aminoindan," J. Med. Chem. 25:1442-46
(1982). .
Dren, A. T. et al., "Local Anesthetic Activity and Acute Toxicity
of N-Substituted 1,2,3,4-Tetrahydro-1-and 2-naphthylamines," J.
Pharmaceutical Sciences 67(6):880-82 (1978). .
Ames, D. E. et al., "The Synthesis of
Alkoxy-1,2,3,4-tetrahydronaphthalene Derivatives. Part I.2-Amino--,
Alkylamino-, and Dialkylamino-derivatives," J. Chem. Soc. 2636-41
(1965). .
Arvidsson, L.-E. et al., "8-Hydroxy-2-(alkylamino)tetralins and
Related Compounds as Central 5-Hydroxytryptamine Receptor
Agonists," J. Med. Chem. 27:45-51 (1984). .
"Arvidsson, L.-E. et al., 8-Hydroxy-2-(di-n-propylamino)tetralin, a
New Centrally Acting 5-Hydroxytryptamine Receptor Agonist," J. Med.
Chem. 24:921-23 (1981). .
McDermed, J. D. et al., "Synthesis and Dopaminergic Activity of
(.+-.)-, (+)-, and
(-)-2-Dipropylamino-5-hydroxy-1,2,3,4-tetrahydronaphthalene," J.
Med. Chem. 19(4):547-49 (1976). .
McDermed, J. D. et al., "Synthesis and Pharmacology of Some
2-Aminotetralins. Dopamine Receptor Agonists," J. Med. Chem.
18(4):362-67 (1975). .
Arvidsson, L.-E. et al.,
"(+)-c-8-Hydroxy-1-methyl-2-(di-n-proplyamino)tetralin: A Potent
and Highly Stereoselective 5-Hydroxytryptamine Receptor Agonist,"
J. Med. Chem. 30:2105-09 (1987). .
Rusterholz, D. B. and C. F. Barfknecht, "Ergoline Congeners as
Potential Inhibitors of Prolactin Release," J. Med. Chem.
19(1):99-102 (1976). .
Cannon, J. G. et al., "Synthesis and Dopaminergic Activity of
(R)-and (S)-4-Hydroxy-2-(di-n-propylamino)indan," J. Med. Chem.
28:515-18 (1985). .
Temple, D. M., "Some New Sympathomimetic Amines: N-Cycloalkyl
Derivatives of 1,2,3,4-Tetrahydro-2-Naphthylamine and of
Noradrenalone," Aust. J. Chem. 20:601-04 (1967)..
|
Primary Examiner: Robinson; Allen J.
Assistant Examiner: O'Sullivan; Peter G.
Attorney, Agent or Firm: Corneglio; Donald
Parent Case Text
CROSS-REFERENCE TO RELATED PATENT APPLICATIONS
This application is a divisional of U.S. Ser. No. 07/784,609, filed
Oct. 29, 1991, now abandoned, which was a continuation of U.S. Ser.
No. 07/571,561, filed Aug. 30, 1990, abandoned, which was the
national phase application of PCT/US89/00974, filed Mar. 15, 1989,
which was a continuation-in-part of U.S. Ser. No. 07/173,130, filed
Mar. 25, 1988, abandoned.
Claims
We claim:
1. A compound of Formula 1 and pharmaceutically acceptable acid
addition salts thereof,
wherein
YR.sub.1 is OR.sub.1 at the 8 position where R.sub.1 is --CH.sub.2
--(C.sub.3-8 cycloalkyl);
R.sub.2 is hydrogen or C.sub.1-3 alkyl;
R.sub.3 is --CH.sub.2 --(C.sub.3-8 cycloalkyl);
R.sub.4 is hydrogen, C.sub.1-8 alkyl, --CH.sub.2 --(C.sub.3-4
cycloalkyl), --(CH.sub.2).sub.3 --R.sub.5 or --CH.sub.2 --CH.sub.2
--X--(CH.sub.2).sub.n CH.sub.3 ;
n is zero to 3
X is oxygen or sulfur; and
R.sub.5 is phenyl, C.sub.1-3 alkoxy, C.sub.1-3 alkyl, 2-thiophene,
3-thiophene, or phenyl substituted with one or two substituent
groups selected from chlorine, bromine or fluorine; and
with the proviso that when R.sub.3 contains more than four carbon
atoms and R.sub.4 is alkyl, said alkyl contains from 1 to 3 carbon
atoms.
2. A compound according to claim 1 wherein R.sub.2 is hydrogen.
3. A compound according to claim 1 wherein R.sub.4 is C.sub.1-8
alkyl or --CH.sub.2 --(C.sub.3-4 cycloalkyl).
4. A compound of Formula 1 and pharmaceutically acceptable acid
addition salts thereof, ##STR3## wherein --YR.sub.1 is
--S--(C.sub.1-3 alkyl) at the 5, 6, 7 or 8 position of the aromatic
ring or OR.sub.1 at the 8 position where R.sub.1 is selected from
the group consisting of C.sub.1-8 alkyl, C.sub.2-8 alkenyl,
--CH.sub.2 --(C.sub.3-8 cycloalkyl) or benzyl;
R.sub.2 is hydrogen or (C.sub.1 -C.sub.3) alkyl;
R.sub.3 is --CH.sub.2 --(C.sub.3 -C.sub.8) cycloalkyl;
R.sub.4 is --(CH.sub.2).sub.m -(2-thiophenyl or 3-thiophenyl); and
m is 2 or 3.
5. A compound according to claim 4 wherein R.sub.2 is hydrogen.
Description
FIELD OF THE INVENTION
The present invention is related to new
1,2,3,4-tetrahydro-2-naphthylamines, to processes for preparing
such compounds, pharmaceutical preparation of such compounds and
the use of such compounds in manufacture of a pharmaceutical
preparation.
BACKGROUND OF THE INVENTION
In depressed patients evidence indicates the neurotransmission in
the central nervous system (CNS) may be disturbed. These
disturbances involve the neurotransmitters noradrenaline (NA) and
5-hydroxytryptamine (5-HT). The drugs most frequently used in the
treatment of depression are considered to act by improving the
neurotransmission of either or both of these physiological agents.
Available data suggests that the enhancement of 5-HT
neurotransmission will primarily improve depressed mood and
anxiety, whereas the enhancement of noradrenaline neurotransmission
will improve retardation symptoms occurring in depressed patients.
In recent years many efforts have been made to develop new drugs
with high selectivity for the improvement of the 5-HT
neurotransmission in the CNS.
The mechanism of action for the drugs generally used today in the
therapy of mental depression is generally believed to be indirect
with the drugs acting by blocking the reuptake of the
neurotransmissers, NA and/or 5-HT, released from nerve terminals in
the CNS, which increases the concentration of these transmitters in
the synaptic cleft and restores an adequate neurotransmission. For
example, the clinically documented antidepression drug, zimelidine
(dimethylamino-1-(4-bromophenyl)-1-(3-pyridyl)propene) acts as such
a reuptake inhibitor with high selectivity for 5-HT neurons.
A fundamentally different way to improve the neurotransmission in
the central 5-HT neurons would be to use a 5-HT receptor agonist
acting directly upon the 5-HT receptors, and particularly the
5-HT.sub.1A receptor. In order to minimize undesired side effects,
a high selectivity for this kind of receptor would be
necessary.
Clinically, 5-HT.sub.1A agonists have also demonstrated anxiolytic
properties. The drug, Buspirone, is the only currently available
marketed 5-HT.sub.1A agonist having anxiolytic activity. This
compound antagonizes dopamine receptors at the same dose it
stimulates 5-HT.sub.1A receptors. A similar drug, Gepirone, also
has dopamine antagonist properties. These dopamine antagonist
properties reduce the clinical utility of these compounds however
because long term treatment with dopamine antagonists can produce
tardive dyskinesia.
The search for new CNS active compounds is focused on finding
compounds with selective 5-HT.sub.1A receptor agonist effects
without detrimentally influencing central dopamine receptors.
Drugs acting on central dopamine transmission are clinically
effective in treating a variety of central nervous system disorders
such as parkinsonism, schizophrenia, and mano-depressive illness.
In parkinsonism, for example, the nigro-neostriatal hypofunction
can be restored by an increase in postsynaptic dopamine receptor
stimulation. In schizophrenia, the condition can be normalized by
achieving a decrease in postsynaptic dopamine receptor stimulation.
Classical antipsychotic agents directly block the postsynaptic
dopamine receptor. The same effect can be achieved by inhibition of
intraneuronal presynaptic events essential for the maintenance of
adequate neurotransmission, transport mechanism and transmitter
synthesis.
In recent years a large body of pharmacological, biochemical and
electrophysical evidence has provided considerable support in favor
of the existence of a specific population of central autoregulatory
dopamine receptors located in the dopaminergic neuron itself. These
receptors are part of a homeostatic mechanism that modulates nerve
impulse flow and transmitter synthesis and regulates the amount of
dopamine released from the nerve endings.
Direct dopamine receptor agonists, like apomorphine, are able to
activate the dopamine autoreceptors as well as the post synaptic
dopamine receptors. The effects of autoreceptor stimulation appear
to predominate when apomorphine is administered at low doses,
whereas at higher doses the attenuation of dopamine transmission is
outweighed by the enhancement of postsynaptic receptor stimulation.
The antipsychotic and antidyskinetic effects in man of low doses of
apomorphine are likely due to the autoreceptor-stimulator
properties of this dopamine receptor agonist. This body of
knowledge indicates dopamine receptor stimulants with a high
selectivity for central nervous dopamine autoreceptors would be
valuable in treating psychiatric disorders.
INFORMATION DISCLOSURE STATEMENT
The following documents could be important in the examination of
this application.
Derwent 12191K (Belgium 893,917) discloses indanyl substituted
imidazole derivatives and tetralyl imidazole derivatives wherein
the aromatic ring of the indanyl and tetralyl groups may be
substituted with various groups including halogen, alkyl (C.sub.1
-C.sub.6, trihaloalkyl, alkoxy and alkylthio. The compounds are
useful in treating atherosclerosis.
British Patent 1,377,356 discloses 8-hydroxy and 8-methoxy
substituted-1,1-dialkyl-2-aminotetralins wherein the amino group is
unsubstituted or substituted with an alkyl C.sub.1 -C.sub.6. These
compounds are useful as analgesics.
Derwent 40378A/23 (British 1,597,140) discloses, among other
compounds, 2-aminotetralins substituted on the aromatic ring with
halogen, di-chloro and additionally hydroxy or an alkanoyloxy
group. These compounds are useful in treating heart conditions
and/or Parkinson's disease.
Switzerland 637,363 (Derwent 729,386) and Switzerland 637,364
discloses, among other compounds, 2-aminotetralins substituted on
the aromatic ring with halogen, di-chloro and additionally hydroxy,
alkyl or other functional groups. These compounds are stimulants of
.alpha.- and .beta.-adrenergic and dopamine receptors rendering
them useful in treating heart failure, cardiac infarct,
hypertension and Parkinson's disease.
Germany 2,333,847 (Derwent 7633V) discloses a very broad scope of
compounds which can include amino tetralins and amino indanes
substituted on the aromatic ring with alkoxy or halogen and
additionally hydroxy, aralkyloxy or acyloxy. These compounds are
water softening agents and corrosion inhibitors in lubricants as
well as CNS-depressants and anti-arrhythmics.
European 272,534-A (Derwent) discloses 2-aminotetralins substituted
in the 8-position by halogen (fluorine, chlorine, bromine or
iodine) among many other compounds within a broad disclosure. These
compounds are useful serotonin antagonists or agonists with high
affinity for cerebral 5-HT.sup.1 receptors rendering them useful in
the treatment of CNS disorders, cognitive deficiencies, Alzheimer's
disease, cardiovascular disorders, pain and intestinal
disorders.
German 2803582 (Derwent 58247B) discloses 2-aminotetralins wherein
the amino group is substituted with inter alia alkyl, or cycloalkyl
and wherein the aromatic ring is substituted with inter alia alkyl,
halogen, di-chloro and additionally with hydroxy or an alkanoyloxy
group. These compounds have a stimulant effect on .alpha.- and
.beta.-adrenoreceptors and on dopamine receptors and are useful in
the treatment of heart failure, cardiac infarct, elevated blood
pressure and Parkinson's disease.
Wikstrom, H., et al., J. Med. Chem. 30, 1115 (1987) discloses
4-hydroxy-and 4-methoxy-2-aminoindanes wherein the amino moiety is
unsubstituted or is substituted with dimethyl or di-n-propyl;
5-hydroxy-2-dimethylaminoindane; and 7-hydroxy-2-aminotetralin
wherein the amino moiety is substituted with dimethyl or
di-n-propyl. This paper focuses on the conformational analysis of
the compounds in relation to their central dopaminergic
effects.
J. G. Canon, et al., J. Med. Chem. 25, 1442-1446 (1982) and J. Med.
Chem. 28, 515-518 (1985) disclose inter alia, 4-hydroxy- and
5-hydroxy-2-di-n-propylindane in a study dealing with the
conformational analysis of a series of 2-aminoindans.
Seeman, et al., Molecular Pharmacology 28, 291-299 (1985) includes
a number of known hydroxy substituted and methoxy substituted
aminotetralins and aminoindans in a D.sub.2 receptor binding
affinity study.
A. T. Dren, et al., J. Pharm. Sci. 67, 880-882 (1978) discloses
among other compounds 2-aminotetralin wherein the amino group is
mono-substituted with cyclopropylmethyl or cyclopropyl and the
aromatic ring is substituted with methoxy at the 5- or 6-position.
These compounds were tested for local anesthetic activity.
D. E. Ames, et al., J. Chem. Soc. 2636 (1965) describes the
synthesis of various di-alkoxy substituted aminotetralins wherein
the alkoxy groups have from 1 to 4 carbon atoms.
6-Methoxy-2-aminotetralin is also described.
L. E. Arvidsson, J. Med. Chem. 27, 45-51 (1984) describes a series
of 2-aminotetralins wherein the amine is substituted with one or
two lower alkyl groups of 1-4 carbon atoms, octyl or benzyl, and
the aromatic ring is substituted 5- and/or 8-position with hydroxy
or lower alkoxy. These compounds were tested as dopamine and
5hydroxytryptamine receptor agonists.
L. E. Arvidsson, et al., J. Med. Chem. 24, 921-923 (1981) discloses
8-methoxy-2-aminotetralins wherein the amino moiety is substituted
with n-propyl, benzyl or di-n-propyl and 2di-n-propylaminotetralins
wherein the aromatic ring is substituted in the 5-, 6-, 7- or
8-position with hydroxy. These compounds were evaluated for their
affect on dopaminergic and .alpha.-adrenergic receptors.
J. D. McDermed, et al., J. Med. Chem. 19, 547-549 (1976) discloses
5,6-dihydroxy and 5-, 6- and 7-hydroxy-2-di-n-propylaminotetralins
in a study of their dopaminergic activity.
J. D. McDermed, et al., J. Med. Chem. 18, 362-367 (1975) discloses
a large series of 2-aminotetralins wherein the aromatic ring is
mono- or di-substituted with hydroxy, methyl or lower alkoxy and
the amine moiety is unsubstituted or substituted with lower alkyl,
benzyl, alkoxyalkyl or forms part of a monocyclic heterocyclic
group. These compounds were evaluated for their dopaminergic
activity.
L. E. Arvidsson, J. Med. Chem. 30, 2105-2109 (1987) evaluates the
5-HT receptor agonist activity of
1-methyl-2-di-n-propylaminotetralins substituted in the 8-position
with hydroxy or methoxy.
D. B. Rusterholz, et al., J. Med. Chem. 19, 99-102 (1976) discloses
5- and/or 8-substituted-2-aminotetralins wherein the 5-or
8-position is substituted with methyl, hydroxy or methoxy. The
effect of these compounds on prolactin release is evaluated.
J. G. Cannon, et al., J. Med. Chem. 28, 515 (1985) describes the
resolution of 4-hydroxy-2-(di-n-propyl)aminoindane, a synthetic
precursor to a potent dopaminergic agonist.
SUMMARY OF THE INVENTION
This invention encompasses compounds of Formula I and
pharmaceutically acceptable acid addition salts thereof, wherein
--YR.sub.1 is one substituent on the 5, 6, 7 or 8 position of the
aromatic ring and is --S(.sub.1 -C.sub.3)alkyl or --OR.sub.1
wherein R.sub.1 is selected from the group consisting of (C.sub.1
-C.sub.8) alkyl, (C.sub.1 -C.sub.8) alkenyl, --CH.sub.2 --(C.sub.3
-C.sub.8) cycloalkyl or benzyl; wherein R.sub.2 is hydrogen or
(C.sub.1 -C.sub.3) alkyl; wherein R.sub.3 is --CH.sub.2 --(C.sub.3
-C.sub.8) cycloalkyl; wherein R.sub.4 is hydrogen, (C.sub.1
-C.sub.8) alkyl, --CH.sub.2 --(C.sub.3 -C.sub.4) cycloalkyl,
--(CH.sub.2).sub.m --R.sub.5 or --CH.sub.2 CH.sub.2
--X--(CH.sub.2).sub.n CH.sub.3 ; wherein n is zero to 3 and m is 2
or 3; wherein X is oxygen or sulfur; and wherein R.sub.5 is phenyl;
phenyl substituted with one or two substituent groups selected from
chlorine, bromine, fluorine, (C.sub.1 -C.sub.3)alkoxy, or (C.sub.1
-C.sub.3)alkyl; 2-thiophene; or 3-thiophene; with the proviso that
when R.sub.3 contains more than 4 carbon atoms and R.sub.4 is alkyl
said alkyl contains from one to 3 carbon atoms.
The compounds of this invention possess selective pharmacological
properties and are useful in treating central nervous system
disorders including antidepression symptoms, anxiolytic symptoms,
panic attacks, obsessive-compulsive disturbances, senile dementia,
emotional disturbances related to dementia disorders, and
stimulation of sexual activity. The compounds of this invention are
also useful to alleviate aggressive behavior, confusional delirious
states and impotence. Certain compounds of this invention
additionally possess blood pressure lowering affects. Processes for
preparation of these compounds, their pharmaceutical use and
pharmaceutical preparations employing such compounds constitute
further aspects of the invention.
According to a preferred embodiment the invention is related to
compounds of Formula I wherein R.sub.3 is --CH.sub.2 --(C.sub.3
-C.sub.8) cycloalkyl, R.sub.4 is (C.sub.1 -C.sub.8) alkyl or
--CH.sub.2 --(C.sub.3 -C.sub.4) cycloalkyl and R.sub.1 is a methyl
group. A more preferred embodiment are compounds of Formula I
wherein R.sub.3 is cyclopropylmethyl, R.sub.4 is (C.sub.1 -C.sub.4)
alkyl or cyclopropylmethyl and R.sub.1 is a methyl group.
An object of the invention is to provide compounds for therapeutic
use, especially compounds having a therapeutic activity in the
central nervous system. Another object is to provide compounds
having an effect on the 5-HT.sub.1A receptor in mammals including
man. A further object of this invention is to provide compounds
having an effect on the subclass of dopamine receptors known as the
D.sub.2 receptor.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of this invention are identified in two ways: by the
descriptive name and reference to labelled structures contained in
appropriate charts. In appropriate situations, the proper
stereochemistry is also represented in the charts.
In this document the parenthetical term (C.sub.n --C.sub.m) is
inclusive such that a compound of (C.sub.1 -C.sub.8) would include
compounds of one to 8 carbons and their isomeric forms. The various
carbon moieties are defined as follows: Alkyl refers to an
aliphatic hydrocarbon radical and includes branched or unbranched
forms such as methyl, ethyl, n-propyl, isopropyl, n-butyl,
isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neo-pentyl,
n-hexyl, isohexyl, n-heptyl, isoheptyl, and n-octyl.
Alkoxy as represented by --OR.sub.1 when R.sub.1 is (C.sub.1
-C.sub.8) alkyl refers to an alkyl radical which is attached to the
remainder of the molecule by oxygen and includes branched or
unbranched forms such as methoxy, ethoxy, n-propoxy, isopropoxy,
n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n-pentoxy, isopentoxy,
neo-pentoxy, n-hexoxy, isohexoxy, n-heptoxy, isoheptoxy, and
n-octoxy.
Alkenyl refers to a radical of an aliphatic unsaturated
hydrocarbons having a double bond and includes both branched and
unbranched forms such as ethenyl, 1-methyl-1-ethenyl, 1-propenyl,
2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-butenyl,
1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl,
1-methyl-4-pentenyl, 3-methyl-1-pentenyl, 3-methyl-2-pentenyl,
1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 1-methyl-4-hexenyl,
3-methyl-1hexenyl, 3-methyl-2-hexenyl, 1-heptenyl, 2-heptenyl,
3-heptenyl, 4-heptenyl, 1-methyl-4-heptenyl, 3-methyl-1-heptenyl,
3-methyl-2-heptenyl, 1-octenyl, 2-octenyl, or 3-octenyl. Cycloalkyl
refers to a radical of a saturated cyclic hydrocarbon such as
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or
cyclooctyl.
It will be apparent to those skilled in the art that compounds of
this invention may contain chiral centers. The scope of this
invention includes all enantiomeric or diastereomeric forms of
Formula I compounds either in pure form or as mixtures of
enantiomers or diastereomers. The compounds of Formula I contain
two asymmetric carbon atoms in the aliphatic ring moiety, including
the ring carbon atoms adjacent to the nitrogen atom. The
therapeutic properties of the compounds may to a greater or lesser
degree depend on the stereochemistry of a particular compound. Pure
enantiomers as well as enantiomeric or diastereomeric mixtures are
within the scope of the invention.
Both organic and inorganic acids can be employed to form non-toxic
pharmaceutically acceptable acid addition salts of the compounds of
this invention. Illustrative acids are sulfuric, nitric,
phosphoric, hydrochloric, citric, acetic, lactic, tartaric,
palmoic, ethanedisulfonic, sulfamic, succinic, cyclohexylsulfamic,
fumaric, maleic, and benzoic acid. These salts are readily prepared
by methods known in the art.
The compounds of this invention may be obtained by one of the
following methods described below and outlined in the appropriate
charts. A compound of the formula, C-1, may be converted into a
compound of Formula I, when R.sub.1 and R.sub.4 are the same, by
alkylation of the nitrogen and oxygen atoms with an appropriate
alkylating agent. The compound of the formula, C-1, may be treated
with an alkyl-halide or tosylate of the formula R.sub.a X, when
R.sub.a is alkyl or cycloalkyl, and when X is Cl, Br, I or TsO, in
an organic solvent such as acetonitrile or acetone and in the
presence of a base such as potassium carbonate or sodium
hydroxide.
Alternatively, the compounds of this invention may be obtained from
a compound of the formula, C-2, by alkylation of the hydroxy moiety
with an appropriate alkylating agent. The starting compound, C-2,
may be treated with an alkyl halide or tosylate R.sub.b X, when
R.sub.b is alkyl, alkenyl, cycloalkyl, or benzyl, when X is Cl, Br,
I or TsO, in an organic solvent such as acetonitrile or acetone and
in the presence of a base such as potassium carbonate or sodium
hydroxide.
In addition, a compound of the formula, C-3, may be converted into
a compound of Formula I, by alkylation of the nitrogen atom with an
appropriate alkylating agent. The starting compound may be treated
with an alkyl halide or tosylate R.sub.c X, when R.sub.c is alkyl,
cycloalkyl, heterocyclic alkyl, ethylalkoxy or ethylthiaalkyl, when
X is Cl, Br, I or TsO, in an organic solvent such as acetonitrile
or acetone and in the presence of a base such as potassium
carbonate or sodium hydroxide, or the starting compound, C-3, may
be treated with a carboxylic acid sodium borohydride complex, when
the carboxylic acid is HOOC--(C.sub.1 -C.sub.7)alkyl,
HOOC--(C.sub.3 -C.sub.8)cycloalkyl, HOOC--(CH.sub.2).sub.p
--R.sub.5, or HOOC--CH.sub.2 --X--(CH.sub.2).sub.n --CH.sub.3, when
p is one or 2, n is zero to 3 and X is oxygen or sulfur.
Alternatively, the starting compound, C-3, may be dissolved in
methanol and treated with an aldehyde and sodium cyanoborohydride,
when the aldehyde is HOC--(C.sub.1 -C.sub.7)alkyl, HOC--(C.sub.3
-C.sub.8)cycloalkyl, HOC--(CH.sub.2).sub.p --R.sub.5, or
HOC--CH.sub.2 --X--(CH.sub.2).sub.n --CH.sub.3, when p is one or 2,
n is zero to 3 and X is oxygen or sulfur.
In addition, an amide of the formula, C-4, when R.sub.d is (C.sub.1
-C.sub.7) alkyl, (C.sub.3 -C.sub.8)cycloalkyl, (CH.sub.2).sub.p
--R.sub.5, or --CH.sub.2 --X--(CH.sub.2).sub.n --CH.sub.3, when p
is one or 2, n is zero to 3 and X is oxygen or sulfur, may be
reduce by a hydride reducing agent such as lithium aluminum hydride
in ether or tetrahydrofuran, diborane in tetrahydrofuran or
QBH.sub.4 (where Q represents tetrabutylammonium ion) in a mixture
of dichloromethane and dichloroethane, to give a compound of
Formula I. Compounds of this invention wherein R.sub.1 Y is
--S(C.sub.1 -C.sub.3)alkyl can be prepared from a compound
corresponding to a C-4 compound wherein OR.sub.1 is replaced by a
hydroxy group by converting the hydroxy group to an amine which is
subsequently converted to bromine via a Sandmeyer reaction. The
bromine substituted intermediate is lithiated using n-butyllithium
in THF or ether and quenched with (C.sub.1
-C.sub.3)alkyl-SS-alkyl(C.sub.1 -C.sub.3) to the alkylthio
substituted compounds.
Starting materials for the compounds, C-1 to C-4, may be obtained
by the methods described below or by methods known in the art. The
known or commercially available ketone, C-5, when R.sub.1 is alkyl,
alkenyl, cycloalkyl, or benzyl, reacts with hydroxylamine in the
presence of base to give the intermediate oxime which is reduced by
catalytic hydrogenation to a compound of formula, C-6. To obtain
the secondary amine a compound of the formula, C-6, is acylated
with a carboxylic acid chloride in the presence of triethylamine
and subsequently reduced by a hydride reducing agent such as
lithium aluminum hydride in ether or tetrahydrofuran, diborane in
tetrahydrofuran or QBH.sub.4 (where Q represents tetrabutylammonium
ion) in a mixture of dichloromethane and dichloroethane.
Alternatively, the ketone, C-5, can be converted directly to the
secondary amine, C-6, by reacting the ketone with a primary amine
of the formula R.sub.e --NH.sub.2, when R.sub.e is alkyl,
cycloalkyl, heterocyclic alkyl, ethylalkoxy or ethylthiaalkyl, with
sodium cyanoborohydride in methanol acidified to about pH 5 with
the addition of a few drops of concentrated acetic acid.
The preparation of the compounds of this invention with an alkyl
group at the one position of the aliphatic ring are obtained by
alkylating a compound of formula, C-7, either via the enamine or by
direct alkylation of the ketone, C-7, under basic conditions, to
give a compound of formula, C-5, converting compound, C-5, into the
secondary amine using methods already described, separation of the
cis- and trans- isomers formed, and finally converting the
secondary amine into the tertiary amine using methods already
described.
A pure enantiomer of compound, C-3, may be prepared by converting
the cis-secondary amine, C-3, into the (-)-O-methylmandelic acid
amide, C-8, followed by chromatographic separation of the two
diastereomers and cleavage by subsequent reaction with potassium
tertbutoxide in tetrahydrofuran with traces of water and methyl
lithium. The secondary amine can be converted into the tertiary
amine using methods already described.
In clinical practice the compounds of the present invention will
normally be administered orally, rectally, or by injection, in the
form of pharmaceutical preparations comprising the active
ingredient either as a free base or as a pharmaceutically
acceptable non-toxic, acid addition salt, such as the
hydrochloride, lactate, acetate, sulfamate salt, in association
with a pharmaceutically acceptable carrier. The use and
administration to a patient to be treated in the clinic would be
readily apparent to a person of ordinary skill in the art.
In therapeutical treatment the suitable daily doses of the
compounds of the invention are 1-2000 mg for oral application,
preferentially 50-500 mg, and 0.1-100 mg for parenteral
application, preferentially 0.5-50 mg.
The compounds of this invention where --OR.sub.1 is in the 8
position in the aromatic ring are very selective 5-HT.sub.1A
receptor agonists having little or no dopaminergic activity. The
IC50 ratio of dopamine D.sub.2 to 5HT.sub.1A in vitro binding data
shown in Table 1 for one compound of this invention,
8-methoxy-2-(N,N-dicyclopropylmethyl)tetralin, demonstrates the
selectivity for the 5-HT.sub.1A receptor. These compounds are
particularly effective anxiolytic and antidepressant agents. Other
uses for these compounds include panic attacks,
obsessive-compulsive disturbances, and senile dementia particularly
the emotional disturbances seen in dementia disorders. In addition,
central 5-HT receptor activation are believed to be involved in
mediating sexual behavior. These compounds would be useful to
stimulate sexual activity and to alleviate impotence.
The compounds of this invention where --OR.sub.1 is in the 5-, 6-,
or 7-position show selective affinity for D.sub.2 receptors. These
compounds are particularly effective in treating psychoses,
mano-depressive illness and parkinsonism.
The compounds of this invention also have been shown to have high
oral potency and a long duration of action. Both these features are
beneficial to effective clinical treatment.
The utility of the compounds of this invention to treat central
nervous system disorders is shown in behavioral and biochemical
activity in reserpine-pretreated rats.
Antagonism of the reserpine-induced "neuroleptic syndrome" in the
rat (gross behavior)
Depletion of the monoamine stores with reserpine brings about a
"neuroleptic syndrome" characterized by hypomotility, catalepsy,
muscle rigidity, hunch-backed posture as well as a number of other
central and peripheral signs of monoamine depletion. The whole or
parts of this syndrome can be reversed by the administration of
drugs that stimulate dopamine or 5-HT receptors directly or
indirectly.
Stimulation of the dopamine receptors, with apomorphine for
example, gives rise to both locomotion and stereotyped behavior
such as sniffing, gnawing and jumping. On the other hand,
stimulation of the 5-HT receptors, with 5-hydroxytryptophane
(5-HTP) combined with MAO-inhibitors for example, gives rise to a
very different behavior. The animals lie flat on the cage floor
exhibiting forward movements with extended forepaws padding,
"piano-playing," and abducted hindlegs, occasionally with some
tremor in the forebody and with Straub tail, stiff tail
erection.
In-vivo determination of rat brain tyrosine and tryptophan
hydroxylation after reserpine pretreatment (biochemically monitored
dopamine and 5-HT receptor activity)
The compounds under evaluation were tested biochemically for
central dopamine and 5-HT receptor (pre- and/or postsynaptic)
stimulating activity. The concept of this biochemical screening
method is that a dopamine or 5-HT-receptor agonist will stimulate
the receptor and through regulatory feedback systems effect a
decline in tyrosine or tryptophan hydroxylating activity,
respectively, and a subsequent reduction in the synthesis rate for
dopamine and 5-HT in the presynaptic neuron. Dopamine and 5-HTP
formation, as determined after in-vivo inhibition of the aromatic
L-amino acid decarboxylase with NSD 1015 (3-hydroxybenzylhydrazine
hydrochloride) are taken as indirect measures of dopamine and
5-HT-synthesis rates, respectively.
Analogous conditions probably exist also for central NA-neurons.
Effects on the dopamine formation in the NA-predominated
hemispheral parts (mainly cortex) may thus be considered to reflect
NA-receptor-mediated changes.
EXPERIMENTAL PROCEDURES
Rats (150-300 g) pretreated with reserpine (5 mg/kg, 18 hours
before) were given the test compounds. Gross behavioral
observations (changes in motility, hindleg abduction, etc.) were
made. Subsequent administration of NSD 1015, decapitation, brain
dissection (corpora striata, the limbic forebrain and the remaining
hemispheral portions (mainly cortex) or rat brain), homogenization,
centrifugation, ion-exchange chromatography and spectrofluorimetric
measurements (all as described in detail by Wikstrom, et al., J.
Med. Chem., 21, 864-867, 1978 and reference cited therein), or by
HPLC/EC, gave the actual dopamine and 5-HTP levels. Several doses
(n-4-6) were tested for each compound and brain area. The dose of a
compound giving 50% of the maximal reduction of the %-HTP level in
the rat brain part was then estimated. These ED50 values are
presented in Table I.
All the compounds in Table 1 were both behaviorally and
biochemically active, producing the above mentioned effects
indicating either central dopamine or 5-HT receptor stimulation.
The absence of significant decreases in the dopamine levels in the
hemispheral brain parts suggests that none of the compounds possess
central NA receptor stimulating effects at the dosage under
consideration.
Certain compounds of the present invention also demonstrate blood
pressure lowering effects, e.g., the compounds of Examples 12, 13,
and 17 when measured in spontaneously hypertensive rats as
described by Grodin, et al., J. Pharm. Pharmacol. 37, 263-265
(1984). Without further elaboration, it is believed that one
skilled in the art can, using the preceding description, practice
the present invention to its fullest extent.
The following detailed examples describe how to prepare the various
compounds and/or perform the various processes of the invention and
are to be construed as merely illustrative, and not limitations of
the preceding disclosure in any way whatsoever. Those skilled in
the art will promptly recognize appropriate variations from the
procedures both as to reactants and as to reaction conditions and
techniques.
EXAMPLES
8-Methoxy-2-(N-cyclopropylmethylamino)tetralin
8-Methoxy-2-aminotetralin hydrochloride (0.5 g, 2.35 mmol) is
dissolved in dichloromethane (50 ml), and triethylamine (3 ml) and
cyclopropanecarboxylic acid chloride (0.95 ml) are added. The
reaction is stopped after 2 hours by the addition of 10% sodium
carbonate (50 ml). The organic layer is separated, washed with
water (50 ml), dried over sodium carbonate, filtered and the
solvent is evaporated yielding the amide as an oil (0.85 g). The
amide is dissolved in dichloromethane (25 ml) and reduced with the
addition of dichloroethane (25 ml) and QBH.sub.4 (2.5 g) (where Q
denotes the tetrabutylammonium ion) under reflux for 6 hours. The
reaction is stopped by the addition of 10% sodium carbonate (100
ml) and dichloromethane (2.times.100 ml). The organic layer is
separated, washed with water (50 ml) dried (sodium carbonate),
filtered and the solvent evaporated yielding the amine (95% purity
according to GC analysis) as an oil (0.47 g). This amine is
converted to the hydrochloride salt with the aid of hydrochloric
acid-saturated ethanol and evaporation. Recrystallization from
ethanol/ether gives white crystals (0.38 g) melting at 214.degree.
C. GC/MS shows M.sup.+ as the base peak at m/e=231.10. Other
prominent peaks appear at m/e=161.05 (m-cyclopropylmethylamine;
48.8%), m/e=160.05 (53.2%) and m/e=159.05 (37.3%).
EXAMPLE 2
8-Methoxy-2-(N,N-di-cyclopropylmethylamino)tetralin
8-Methoxy-2-(N-cyclopropylmethylamino)tetralin hydrochloride (0.36
g, 1.35 mmol) is dissolved in dichloromethane (50 ml), and
triethylamine (1 ml) and cyclopropanecarboxylic acid chloride (0.35
ml) are added. The reaction is stopped after 2 hours by the
addition of 10% sodium carbonate (50 ml). The organic layer is
separated, washed with water (50 ml), dried (sodium carbonate),
filtered and the solvent is evaporated leaving the amide as an oil
(0.47 g), which is dissolved in dichloromethane (25 ml) and reduced
with the addition of dichloroethane (25 ml) and QBH.sub.4 (2.5 g)
(where Q denotes the tetrabutylammonium ion) under reflux for 2
hours. The reaction is not complete at this time according to GC
analysis, and further addition of QBH.sub.4 (2.5 g) and
dichloroethane (25 ml) is made. The reaction is stopped after one
night's reflux by the addition of 10% sodium carbonate (100 ml) and
dichloromethane (2.times.100 ml). The organic layer is separated,
washed with water (50 ml), dried (sodium carbonate), filtered and
the solvent is evaporated yielding the amine as an oil (0.40 g).
The amine is chromatographed (silica gel, 40 g) eluting first with
petroleum ether:ether (3:1) and then with ether. The fractions
containing pure product are pooled and the solvent is evaporated.
The residual amine is converted into the hydrochloride by the
addition of hydrochloric acid-saturated ethanol and evaporation.
Recrystallization from ethyl acetate/ether gives white crystals
(114 mg) melting at 174.degree.-176.degree. C. GC/MS shows M.sup.+
at m/e=285.25 (54.8%), the base peak at m/e=136.10. Other prominent
peaks appear at m/e=244.15 (m-cyclopropyl; 25.0%), m/e=161.05
(m-(di-cyclopropylmethylamine); 63.5%).
The remaining fractions are collected and the solvent is evaporated
yielding 150 mg of an oil holding 70% of the intermediate amide.
The oil is dissolved in dry ether (10 ml) and reduced with lithium
aluminum hydride and converted into the hydrochloride salt as
described above and recrystallization as above gives 126 mg of
white crystals with the same characteristics as those obtained
initially.
EXAMPLE 3
cis-5-Methoxy-1-methyl-2-(N-cyclopropylmethylamino)tetralin
To a solution of 5-methoxy-1-methyl-2-tetralone (2.0 g) in absolute
ethanol (50 ml) are added acetic acid (1.9 g),
cyclopropylmethylamine (2.0 g) and 4 .ANG. molecular sieves. The
mixture is heated in a closed flask at 80.degree. C. for one hour.
The molecular sieves are filtered off and the solution is
hydrogenated (PtO.sub.2) at atmospheric pressure. The catalyst is
filtered off (Celite) and the volatiles are evaporated. Dilute
hydrochloric acid (50 ml) is added to the solid residue. The
resulting acidic solution is washed with ether, made basic 5%
sodium hydroxide and extracted twice with ether. The ether extracts
are combined, dried (sodium sulfate) and evaporated. The resulting
crude base is eluted through an alumina column with ether-light
petroleum (1:4).
EXAMPLE 4
cis-5-Methoxy-1-methyl-2-(N,N-dicyclopropylmethylamino)tetralin
hydrochloride
Cyclopropanecarboxylic acid chloride (0.49 g) in dry ether (10 ml)
is added to a solution of
cis-5-methoxy-1-methyl-2-(N-cyclopropylmethylamino)tetralin (400
mg) and triethylamine (0.49 g) in dry ether (80 ml). After 30
minutes at room temperature the reaction mixture is filtered and
the ether is evaporated. The resulting crude amide is passed
through an alumina column eluted with ether. The purified amide
dissolved in dry THF (20 ml) is added to a suspension of lithium
aluminum hydride (1.0 g) in dry THF (30 ml) under N.sub.2. After
stirring under reflux for 3 hours, the reaction mixture is
hydrolyzed, the precipitate is filtered off and the solvent is
evaporated. The oily residue is chromatographed on an alumina
column with ether-light petroleum (1:1). The hydrochloride is
prepared and recrystallized from ethanol-ether to give the title
compound.
EXAMPLE 5
(+) and
(-)-cis-5-Methoxy-1-methyl-2-(N,N-dicyclopropylmethylamino)tetralin
hydrochloride
(-)-cis-5-Methoxy-1-methyl-2-(N,N-dicyclopropylmethylamino)tetralin
hydrochloride
R-(-)-O-Methylmandelic acid chloride (4.1 g), prepared from
R-(-)-O-methylmandelic acid by treatment with thionylchloride at
20.degree. C. for 10 hours, dissolved in dichloromethane (5 ml) is
added at room temperature to a stirred mixture of
(.+-.)-cis-5-methoxy-1-methyl-2-(N-cyclopropylamino)tetralin (3.0
g), dichloromethane (25 ml), water (25 ml) and 5% aqueous sodium
hydroxide (12 ml). After stirring for 1.5 hour the phases are
separated and the organic phase is washed once with water then
dried (magnesium sulfate), filtered and evaporated. Ether (15 ml)
is added to the residue and one of the diastereomeric amides
precipitated (1.2 g). The precipitate is collected by filtration
and then recrystallized from acetone to give 1.0 g of one of the
diastereomers. The filtrates from the treatment with ether and
acetone are combined and evaporated. This oily residue is
chromatographed on a silica gel column with ether/light petroleum
(50:50). The fractions containing one of the diastereomers, which
is eluted first are combined and the solvent is evaporated to give
0.6 g of one of the diastereomeric amides. This diastereomer shows
to be the same diastereomeric amide (TLC) as is isolated by
precipitation from ether (see above). The diastereomeric amide (1.6
g) is dissolved in dry tetrahydrofuran (40 ml) and kept at
-8.degree. C. under nitrogen. To this solution is added
potassium-tert-butoxide (21.1 g) and water (0.60 ml) with the
addition divided in seven portions over 12 days. Thirteen days
after the first addition of reagents ice, water and ether is added
to the reaction mixture until 2 layers form. The phases are
separated and the organic layer is washed with 1M hydrochloric
acid, saturated aqueous sodium bicarbonate, dried (magnesium
sulfate), filtered and evaporated. The residue, dissolved in
ether-light petroleum (50:50), is passed through a silica gel
column and eluted first with ether-light petroleum (50:50) and then
with ether, yielding a solid (0.55 g) after evaporation. To this
solid (0.56 g), dissolved in dry tetrahydrofuran (40 ml) at
8.degree. C. and under nitrogen, methyl lithium (0.0054 mol) is
added under stirring. The mixture is stirred for 10 minutes, then
extracted with saturated aqueous NH.sub.4 Cl. The phases are
separated and the organic layer is extracted with 5M hydrochloric
acid. The combined aqueous layers are made basic with 5M sodium
hydroxide and extracted with ether. The organic layer is dried
(sodium sulfate) and filtered. Hydrochloric acid-saturated ether is
added giving a precipitate which is recrystallized giving
(-)-cis-5-methoxy-1-methyl-2-(N-cyclopropylmethylamino)tetralin
hydrochloride.
Cyclopropanecarboxylic acid chloride (0.28 g) in dry ether (5 ml)
is slowly added at 5.degree. C. to a solution of
(-)-cis-5-methoxy-1-methyl-2-(N-cyclopropylmethylamino)tetralin
(0.35 g), triethylamine (0.31 g) and dry ether (45 ml). The mixture
is stirred at room temperature for one hour, the
triethylammoniumchloride formed is filtered off and the solvent
evaporated. The residue (0.40 g) dissolved in dry tetrahydrofuran
(10 ml) is added to a suspension of lithium aluminum hydride (0.80
g) in dry tetrahydrofuran (40 ml) under nitrogen. After stirring
under reflux for 5 hours, the mixture is hydrolyzed, the
precipitate is filtered off, and the solvent is evaporated. The
residue is passed through an alumina column with ether/light
petroleum (20:80), and the amine is precipitated as the
hydrochloride and recrystallized from ethanol-ether to give
(-)-cis-5-methoxy-1-methyl-2-(N,N-dicyclopropylmethylamino)tetralin
hydrochloride.
EXAMPLE 6
(.+-.)-cis-7-methoxy-1-methyl-2-(N-cyclopropylmethylamino)tetralin
To a solution of 7-methoxy-1-methyl-2-tetralone (2.0 g) in absolute
ethanol (50 ml) are added acetic acid (1.85 g, 31.5 mmol),
cyclopropylmethylamine (1.85 g) and 4 .ANG. molecular sieves. The
mixture is refluxed for 3.5 hours. The molecular sieves are
filtered off and the solution is hydrogenated with 0.3 g PtO.sub.2
in a Parr apparatus. The catalyst is filtered off (Celite) and the
volatiles are evaporated. The resulting crude base is eluted
through an silica gel column with methanol, affording an oil of 80%
isomeric purity (GC). The hydrochloride is prepared and
recrystallized 2 times from methanol-ether.
EXAMPLE 7
(.+-.)-cis-7-methoxy-1-methyl-2-(N,N-dicyclopropylmethylamino)tetralin
Sodium borohydride (0.41 g, 10.1 mmol) is added portionwise to a
stirred solution of cyclopropanecarboxylic acid chloride (2.4 g) in
dry benzene (20 ml) under N.sub.2, keeping the temperature below
20.degree. C. After 2 hours,
(.+-.)-cis-7-methoxy-1-methyl-2-(cyclopropylmethylamino)tetralin
(0.5 g) is added and the mixture is refluxed for 4 hours and then
treated with 10% sodium bicarbonate solution. The benzene layer is
dried (sodium sulfate) and the solvent is evaporated. The
hydrochloride salt is prepared and recrystallized from
methanol-ether.
EXAMPLE 8
Preparation of Soft Gelatine Capsules
500 g of active substance are mixed with 500 g of corn oil,
whereupon the mixture is filled in soft gelatine capsules, each
capsule containing 100 mg of the mixture.
EXAMPLE 9
Preparation of Tablets
0.5 kg of active substance are mixed with 0.2 kg of silicic acid of
the trademark Aerosil. Potato starch (0.45 kg) and lactose (0.5 kg)
are mixed therewith and the mixture is moistened with a starch
paste prepared from 50 g of potato starch and distilled water,
whereupon the mixture is granulated through a sieve. The granulate
is dried and sieved, whereupon 20 g of magnesium stearate are mixed
into it. Finally the mixture is pressed into tablets each weighing
172 mg.
EXAMPLE 10
Preparation of a Syrup
100 g of active substance are dissolved in 300 g of 95% ethanol,
whereupon 300 g of glycerol, aroma and coloring agents (q.s.) and
1000 ml of water are mixed therein. A syrup is obtained.
EXAMPLE 11
Preparation of an injection solution
Active substance (1 g), sodium chloride (0.8 g) and ascorbic acid
(0.1 g) are dissolved in sufficient amount of distilled water to
give 100 ml of solution. This solution, which contains 10 mg of
active substance per ml, is used in filling ampoules, which are
sterilized by heating at 120.degree. C. for 20 minutes.
EXAMPLE 12
(+)-R-8-Methoxy-2-(di-cyclopropyl-methylamino)tetralin
The resolution is performed on 8-methoxy-2-(benzylamino)tetralin
with the aid of (-)-di-p-toluoyltartaric acid according to
Karlsson, et al., Acta Chem. Scand., B 42, 231-236 (1988). The
enantiomers of 8-methoxy-2-(benzylamino)tetralin are debenzylated,
yielding the corresponding enantiomers of
8-methoxy-2-aminotetralin, i.e., R-(+)- and
S-(-)-8-methoxy-2-aminotetralin.
The primary amine (+)-R-8-methoxy-2-aminotetralin (3.29 g) is
acylated with cyclopropanecarboxylic acid chloride (1.8 ml) and the
amide produced (3.63 g) is reduced with QBH.sub.4 as described in
above, yielding the secondary amine, which is acylated again in the
same way with cyclopropanecarboxylic acid chloride (3.2 ml). The
amide produced (3.57 g) is dissolved in dry THF (25 ml) and reduced
with LiAlH.sub.4 at room temperature. Usual workup yields the raw
tertiary amine product (2.9 g), which is chromatographed (SiO.sub.2
; eluting with CH.sub.2 Cl.sub.2 :MeOH (19:1)), yielding pure
product (2.1 g) as an oil, which is converted to its hydrochloride
with HCl-saturated EtOH and evaporation of the solvent and excess
acid. No crystals are obtained in an attempt to crystallize the
product. The optical rotation is: .alpha..sub.D.sup.22 =+68.degree.
(c 1.0, MeOH).
GC/MS shows M.sup.+ at m/e=285 (61%) and the base peak at m/e=136.
Other prominent peaks appear at m/e=244 (30%), 161 (72%) and
m/e=160 (42%).
EXAMPLE 13
(-)-R-8-Methoxy-2-(di-cyclopropylmethylamino)tetralin
The primary amine (-)-R-8-methoxy-2-aminotetralin (5.0 g) is
converted into the secondary amine
(-)-R-8-methoxy-2-(cyclopropylmethylamino)tetralin, which is
further converted into the tertiary amine
(-)-R-8-methoxy-2-(di-cyclopropylmethylamino)tetralin (2.42 g) as
described for the corresponding (+)-enantiomer in Example 3 above.
The optical rotation is: .alpha..sub.D.sup.22 =-66.degree. (c 1.0,
MeOH).
GC/MS shows M.sup.+ at m/e=285 (83%) and the base peak at m/e=136.
Other prominent peaks appear at m/e=244 (33%), 161 (67%) and
m/e=160 (40%).
EXAMPLE 14
8-Methoxy-2-(N-cyclopropylmethyl-N-ethylamino)tetralin
8-Methoxy-2-(cyclopropylmethylamino)tetralin (200 mg) is dissolved
in CH.sub.2 Cl.sub.2 (25 ml) and the solution is basified by the
addition of Et.sub.3 N (3 ml). Acetylchloride (150 .mu.l) is added
and the reaction mixture is left stirring for 3 hours. 10% Na.sub.2
CO.sub.3 is added and the raw amide product is extracted to the
organic layer, which is dried and filtered. The organic solvent is
removed by evaporation yielding 210 mg of the amide as an oil,
which is dissolved in dry ether (10 ml). This solution is added to
a suspension of LiAlH.sub.4 (0.3 g) in dry ether (10 ml) and the
temperature is kept at about 0.degree. C. with an ice bath. Usual
workup (0.3 ml water, 0.3 ml 15% NaOH, 0.9 ml water, filtration and
ether extraction) gives 188 mg of an oil, which is chromatographed
(200 g SiO.sub.2 ; eluting with CH.sub.2 Cl.sub.2 : MeOH (19:1)),
yielding the product as an oil (66 mg).
GC/MS shows M.sup.+ at m/e=259 (70%) and the base peak at m/e=161.
Other prominent peaks appear at m/e=244 (33%) and m/e=160
(30%).
EXAMPLE 15
8-Methoxy-2-(N-cyclopropylmethyl-N-n-propylamino)-tetralin
8-Methoxy-2-(n-propylamino)tetralin (350 mg) is dissolved in
CH.sub.2 Cl.sub.2 (20 ml) and Et.sub.3 N (1 ml) and
cyclopropanecarboxylic acid chloride (0.5 ml) are added. Workup
gives the amide (0.6 g) as an oil. The amide is dissolved in dry
ether and reduced with LiAlH.sub.4 (0.9 g). The reaction is
quenched after 2 hours in the usual way (0.9 ml H.sub.2 O, 0.9 ml
15% NaOH and 2.7 ml H.sub.2 O) and workup yields an oil, which is
chromatographed on SiO.sub.2 (70 g), eluting with petroleumether:
ether (1:1). The fractions containing pureproduct are pooled and
the solvent is evaporated yielding an oil (210 mg) which is
converted to the hydrochloride with HCl-saturated EtOH and
evaporation of the solvent. Crystals (170 mg) are obtained from
aceton: ether, and they melt at 143.degree.-145.degree. C.
GC/MS shows M.sup.+ at m/e=273.15 (24.5%) and the base peak at
m/e=161.05. Other prominent peaks appear at m/e=245.05 (14.3%),
m/e=244.05 (87.1%) and m/e=162.05 (18.8%).
EXAMPLE 16
7-Methoxy-2-(N-cyclopropylmethyl-N-n-propylamino)-tetralin
7-Methoxy-2-(n-propylamino)tetralin (500 mg) is dissolved in
CH.sub.2 Cl.sub.2 (25 ml) and the solution is basified by the
addition of Et.sub.3 N (3 ml). Cyclopropanecarboxylic acid chloride
(195 .mu.l) is added and the reaction mixture is left stirring for
4 hours. 10% Na.sub.2 CO.sub.3 is added and the raw amide product
is extracted to the organic layer, which is dried and filtered. The
organic solvent is removed by evaporation yielding 500 mg of the
amide (GC/MS shows M.sup.+ at m/e=287.15 (0.3%) and the base peak
at m/e=160.10) as an oil, which is dissolved in 1,2-dichloroethane
(50 ml). To this solution is added QBH.sub.4 (where Q means
tetrabutylammonium) (5.0 g) dissolved in CH.sub.2 Cl.sub.2 (50 ml).
The reaction mixture is refluxed for 36 hours and is then chilled
to room temperature and extracted with water several times. The
solvents of the organic phase are evaporated and to the residue is
added ether. The ether phase is washed with water several times,
separated, dried (Na.sub.2 SO.sub.4), filtered and the solvent is
evaporated to give 453 mg of an oil, which is chromatographed (200
g SiO.sub.2 ; eluting with petroleumether:ether (9:1), yielding the
product as an oil. This oil is converted to the hydrochloride with
HCl-saturated EtOH and evaporation to yield an oil (436 mg).
GC/MS shows M.sup.+ at m/e=273.15 (27.1%) and the base peak at
m/e=244.15. Other prominent peaks appear at m/e=161.10 (76.9%).
EXAMPLE 17
8-Methoxy-2-(N-cyclopropylmethyl-N-(2-thiophenethyl)-amino)tetralin
8-Methoxy-2-aminotetralin (800 mg) is stirred in a two phase system
(10% Na.sub.2 CO.sub.3 and CH.sub.2 Cl.sub.2) and 2-thiopheneacetic
acid chloride (1 g) is added. The reaction mixture is stirred for 2
hours and then the organic phase is separated, dried (Na.sub.2
SO.sub.4) and filtered. The solvent is evaporated to give the amide
as an oil (1.5 g). The amide is reduced with QBH.sub.4 (1 g) in a
refluxing (8 hours) mixture of CH.sub.2 Cl.sub.2 (50 ml) and
1,2-dichloroethane (50 ml). The reaction mixture is chilled to room
temperature and the organic layer is washed several times with
water. The organic layer is separated and the solvents are
evaporated, yielding an oil, which is treated with EtOAc and water.
This mixture is acidified with HCl (10%) and stirred for 30 minutes
and then the mixture is basified. The organic layer is separated,
dried (Na.sub.2 SO.sub.4) and filtered. The solvent is evaporated
to give the amine as an oil (900 mg). This oil (400 mg) is
dissolved in CH.sub.2 Cl.sub.2 (25 ml) and Et.sub.3 N (1 ml) and
cyclopropanecarboxylic acid chloride (1.0 ml) is added and the
reaction mixture is left stirring for one hour. 10% Na.sub.2
CO.sub.3 is added and the raw amide produce is extracted to the
organic layer, which is dried and filtered. The organic solvent is
removed by evaporation yielding 600 mg of the amide as an oil,
which is chromatographed (SiO.sub.2 and eluting with
petroleumether: ether (2:1)), yielding 270 mg of the pure amide.
This amide (270 mg) is dissolved in 1,2-dichloroethane (20 ml). To
this solution is added QBH.sub.4 (where Q means tetraethylammonium)
(1.0 g) dissolved in CH.sub.2 Cl.sub.2 (20 ml). The reaction
mixture is refluxed for 12 hours and is then chilled to room
temperature and extracted with water several times. The solvents of
the organic phase are evaporated and to the residue is added EtOAc
(20 ml). The organic phase is washed with water several times,
separated, dried (Na.sub.2 SO.sub.4), filtered and the solvent is
evaporated to give 220 mg of an oil, which is chromatographed (20 g
SiO.sub.2 ; eluting with petroleumether:ether (1:1)), yielding the
product as an oil (160 mg). This oil is converted to the
hydrochloride with HCl-saturated EtOH and evaporation of the
solvent to yield an oil (170 mg).
GC/MS shows M.sup.+ at m/e=340.20 (0.1%), m/e=341.10 (0.1%), and
the base peak at m/e=161.10. Other prominent peaks appear at
m/e=245.20 (11.6%) and m/e=244.20 (63.8%).
EXAMPLE 18
5-Methoxy-2-(cyclopropylmethylamino)tetralin
5-Methoxy-2-aminotetralin (972 mg) is dissolved in CH.sub.2
Cl.sub.2 (20 ml) and Et.sub.3 N (3 ml) is added together with
cyclopropanecarboxylic acid chloride (550 .mu.l). The reaction
mixture is left stirring for one hour. 10% Na.sub.2 C.eta..sub.3 is
added and the raw amide product is extracted to the organic layer,
which is dried and filtered. The organic solvent is removed by
evaporation yielding 1.16 g of the amide as an oil, which is
chromatographed (SiO.sub.2 and eluting with CH.sub.2 Cl.sub.2 :MeOH
(45:1)), yielding 0.98 mg of the pure amide (GC/MS shows M.sup.+ at
m/e=245 (61%) and the base peak at m/e=160. Other prominent peaks
appear at m/e=159 (26%), m/e=145 (19%) and m/e=129 (18%)). This
amide (0.98 g) is dissolved in 1,2-dichloroethane (30 ml). To this
solution is added QBH.sub.4 (where Q means tetrabutylammonium) (2.0
g) dissolved in CH.sub.2 Cl.sub.2 (30 ml). The reaction mixture is
refluxed for 24 hours and then chilled to room temperature and
extracted with water several times. The solvents of the organic
phase are evaporated and to the residue is added EtOAc (20 ml). The
organic phase is washed with water several times, separated, dried
(Na.sub.2 SO.sub.4), filtered and the solvent is evaporated to give
800 mg of an oil, which is chromatographed (200 g SiO.sub.2 ;
eluting with CH.sub.2 Cl.sub.2 :MeOH (19:1)), yielding the product
as an oil (800 mg).
GC/MS shows M.sup.+ as the base peak at m/e=231. Other prominent
peaks appear at m/e=161 (62%), m/e=160 (83%), m/e=159 (64%), and
m/e=104 (92%).
EXAMPLE 19
5-Methoxy-2-(dicyclopropylmethylamino)tetralin
5-methoxy-2(dicyclopropylmethylamino)tetralin (410 mg) is dissolved
in CH.sub.2 Cl.sub.2 (20 ml) and Et.sub.3 N (3 ml) is added
together with cyclopropanecarboxylic acid chloride (400 .mu.l). The
reaction mixture is left stirring for 48 hours. 10% Na.sub.2
CO.sub.3 is added and the raw amide product is extracted to the
organic layer, which is dried and filtered. The organic solvent is
removed by evaporation yielding 520 of the amide as an oil. This
raw amide (520 mg) is dissolved in dry THF (15 ml) and this
solution is added dropwise to a suspension of LiAlH.sub.2 (0.5 g)
in dry THF (10 ml). The reaction mixture is stirred at room
temperature for one hour and usual workup gives 385 mg of the
desired product as an oil (GC/MS shows M.sup.+ at m/e=285.20 (40%),
base peak at m/e=136.05. Other prominent peaks appear at m/e=244.10
(30.1%), m/e=161.05 (37.9%, m/e=), m/e=160.15 (30.2%), and
m/e=159.05 (13.2%). The product is converted to a crystalline
hydrochloride and crystals, melting at 150-153.degree. C., are
obtained from EtOH: ether.
EXAMPLE 20
5-Methoxy-2(N-cyclopropylmethyl-N-n-propylamino)-tetralin
5-Methoxy-2-(cyclopropylmethylamino)tetralin (390 mg) is dissolved
in CH.sub.2 Cl.sub.2 (20 ml) and Et.sub.3 N (3 ml) is added
together with propionic acid chloride (300 .mu.l). The reaction
mixture is left stirring for 5 hours. 10% Na.sub.2 CO.sub.3 is
added and the raw amide product is extracted to the organic layer,
which is dried and filtered. The organic solvent is removed by
evaporation yielding 469 mg of the amide as an oil. This raw amide
(469 mg) is dissolved in dry ether (15 ml) and this solution is
added dropwise to a suspension of LiAlH.sub.4 (0.45 g) in dry ether
(10 ml). The reaction mixture is stirred at room temperature for
one hour and usual workup gives 324 mg of the desired product as an
oil, which is chromatographed (SiO.sub.2 and eluting with CH.sub.2
Cl.sub.2 :MeOH (19:1), yielding 201 mg of the desired product as an
oil. GC/MS shows M.sup.+ at m/e=273.20 (25.0%), base peak at
m/e=244.25. Other prominent peaks appear at m/e=245.25 (18.6%),
m/e=244.05 (87.1%) and m/e=161.15 (75.3%).
EXAMPLE 21
(+)-cis-1S,2R-5-Methoxy-1-methyl-2-(N-cyclopropylmethyl-N-n-propylamino)tet
ralin
(+)-cis-1S, 2R-5-Methoxy-1-methyl-2-(n-propylamino)tetralin (500
mg) is dissolved in CH.sub.2 Cl.sub.2 (20 ml) and Et.sub.3 N (3 ml)
is added together with cyclopropanecarboxylic acid chloride (300
.mu.l). The reaction mixture is left stirring for one hour. 10%
Na.sub.2 CO.sub.3 is added and the raw amide product is extracted
to the organic layer, which is dried and filtered. The organic
solvent is removed by evaporation yielding 550 mg of the amide as
an oil. This raw amide (550 mg) is dissolved in dry ether (15 ml)
and this solution is added dropwise to a suspension of LiAlH.sub.4
(0.60 g) in dry ether (10 ml). The reaction mixture is stirred at
room temperature overnight and usual workup gives 483 mg of the
desired product as an oil, which is chromatographed (100 g
SiO.sub.2 and eluting with hexane:ether (3:1)), yielding the
desired product as an oil (280 mg). This oil is converted to the
hydrochloride salt, but no crystals are achieved.
GC/MS shows M.sup.+ at m/e=287.15 (25.8%) and the base peak at
m/e=258.15. Other prominent peaks appear at m/e=259.15 (19.5%),
m/e=176.10 (12.4%), m/e=175.10 (88.6%) and m/e=174.20 (17.4%), The
optical rotation is measured and found to be: .alpha..sub.D.sup.22
=+38.degree. (c 1.0, MeOH).
EXAMPLE 22
(+)-cis-1S,2R-5-Methoxy-1-methyl-2-(cyclopropylmethylamino)tetralin
(+)-cis-1S,2R-5-Methoxy-1-methyl-2-aminotetralin (970 mg) is
dissolved in CH.sub.2 Cl.sub.2 (20 ml) and Et.sub.3 N (3 ml) is
added together with cyclopropanecarboxylic acid chloride (500
.mu.l). The reaction mixture is left stirring for one hour. 10%
Na.sub.2 CO.sub.3 is added and the raw amide product is extracted
to the organic layer, which is dried and filtered. The organic
solvent is removed by evaporation yielding 1.0 g of the amide as an
oil. This raw amide (1.0 g) is dissolved in 1,2-dichloroethane (60
ml). To this solution is added QBH.sub.4 (where Q means
tetrabutylammonium) (1.4 g) dissolved in CH.sub.2 Cl.sub.2 (60 ml).
The reaction mixture is refluxed for 48 hours and is then chilled
to room temperature and extracted with water several times. The
solvents of the organic phase are evaporated and to the residue is
added trichlorethylene. The organic phase is washed with water
several times, separated, dried (Na.sub.2 SO.sub.4), filtered and
the solvent is evaporated to give 840 mg of an oil, which is
converted to the hydrochloride with HCl-saturated EtOH and
evaporation to yield crystals (750 mg) melting at 212.degree.
C.
GC/MS shows M.sup.+ at m/e=245.15 (53.5%) and the base peak at
m/e=148.10. Other prominent peaks appear at m/e=190.20 (15.6%),
m/e=175.10 (18.2%), m/e=174.10 (44.8%), m/e=173.20 (10.3%) and
m/e=159.10 (45.9%). The optical rotation is measured and found to
be: .alpha..sub.D.sup.22 =+49.1.degree. (c 1.0, MeOH).
EXAMPLE 23
(+)-cis-1S,2R-5-Methoxy-1-methyl-2-(N-cyclopropylmethyl-N-(3-methoxyphenyle
thyl)amino)tetralin
(+)-cis-1S,2R-5-Methoxy-1-methyl-2-(cyclopropylmethylamino)tetralin
(50 mg) was dissolved in CH.sub.2 Cl.sub.2 (5 ml) and 10% NaOH (5
ml) was added together with 3-methoxyphenylacetic acid chloride (50
.mu.l). The reaction mixture was left stirring for one hour. The
raw amide product was extracted to the organic layer, which was
dried and filtered. The organic solvent was removed by evaporation
yielding 60 mg of the amide as an oil. This raw amide (60 mg) was
dissolved in 1,2-dichloroethane (10 ml). To this solution was added
QBH.sub.4 (where Q means tetraethylammonium) (200 mg) dissolved in
CH.sub.2 Cl.sub.2 (30 ml). The reaction mixture was refluxed
overnight and was then chilled to room temperature and extracted
with water several times, separated, dried (Na.sub.2 SO.sub.4),
filtered and the solvent was evaporated to give 60 mg of the
desired product as an oil, which was chromatographed (15 g
SiO.sub.2 and eluting with hexane:ether (3:1)), yielding the
desired product as an oil (20 mg). This oil was converted to the
hydrochloride salt, but no crystals were achieved.
GC/MS shows M.sup.+ at m/e=379.20 (0.1%) and the base peak at
m/e=258.20. Other prominent peaks appeared at m/e=259.20 (19.0%),
m/e-176.10 (8.6%) and m/e=175.10 (65.3%). The optical rotation was
measured and was found to be .alpha..sub.D.sup.22 =+35.degree. (c
1.0, MeOH).
EXAMPLE 24
(+)-R-8-Methoxy-2-(N-cyclopropylmethyl-N-(3-methoxyphenylethyl)amino)-tetra
lin
(+)-R-8-Methoxy-1-methyl-2-(cyclopropylmethylamino)tetralin (250
mg) was dissolved in CH.sub.2 Cl.sub.2 (25 ml) and 10% NaOH (25 ml)
was added together with a 3-methoxyphenylacetic acid chloride (0.4
g). The reaction mixture was left stirring for 2 days. The raw
amide product was extracted to the organic layer, which was dried
and filtered. The organic solvent was removed by evaporation
yielding 400 mg of the amide as an oil. This raw amide was
chromatographed (SiO.sub.2 and eluting with petroleumether:ether
(3:1)). The fractions containing pure product were pooled and the
solvent was evaporated yielding an oil (250 mg). The amide oil (250
mg) was dissolved in dry ether (10 ml). To this solution was added
LiAlH.sub.4 (100 mg). Usual workup gave the desired product as an
oil (100 mg).
GC/MS showed M-1 at m/e-364.15 (0.1%) and the base peak at
m/e=161.00. Other prominent peaks appeared at m/e-245.05 (16.2%)
and m/e=244.05 (87.2%).
EXAMPLE 25
7-Methylthio-2-(N-cyclopropylmethyl(-N-n-propylamino)-tetralin
7-Bromo-2-(di-n-propylamin)tetralin HCl (600 mg) was converted to
the base with 10% Na.sub.2 CO.sub.3 and extraction with CH.sub.2
Cl.sub.2. The organic layer was dried and filtered and the solvent
was evaporated under reduced pressure. The residual oil was
dissolved in dry THF (40 ml) and poured into a flask equipped with
N.sub.2 (.sub.g) inlet, a drug funnel, a thermometer and septum for
syringe injections of reagents and sample collection. This flask
was chilled to -78.degree. C. and n-BuLi in hexane (1.4M, 3 ml) was
injected through the septum. The reaction mixture was stirred for
0.5 hour for the halogen-lithium exchange to take place. This was
checked with a small sample quenched in water and GC analysis.
Dimethylsulfide (0.5 ml) was added dropwise from the funnel during
30 minutes at -78.degree. C. The CO.sub.2 (s)-bath was removed and
the temperature was allowed to reach room temperature before the
reaction was quenched with water. Extractive workup yielded in oil
(700 mg), which contained 2-(di-n-propylamino)tetralin and the
desired product in an approximative ration of 45:55. This raw oil
was chromatographed and the fractions containing pure product were
pooled and the solvent was evaporated yielding 110 mg of the
product as an oil, which was used in the next step without further
purification. The oil (95 mg) was dissolved in CH.sub.2 Cl.sub.2
(10 ml) and excess Br.sub.2 (35 .mu.l) was added. The organic phase
was extracted with 10% Na.sub.2 CO.sub.3 and separated. Excess
Br.sub.2 was removed with the addition of anisole (1 ml). The
product in the organic phase was then extracted to 10% HCl and the
acidic organic phase (containing the brominated anisoles) was
discarded. The acidic water was basified (10% Na.sub.2 CO.sub.3)
and extracted with ether, dried (Na.sub.2 CO.sub.3), filtered and
the solvent was evaporated, yielding 40 mg of an oil.
GC/MS showed M.sup.+ at m/e=235 (60%) and the base peak at m/e=129.
Other prominent peaks appeared at m/e-206 (52%), m/e-192 (20%),
m/e-177 (45%), m/e-176 (30%), m/e=175 (15%), m/e=151 (25%), m/e=150
(35%) and m/e=130 (50%).
The secondary amine produced (40 mg, 0.17 mmol) was dissolved in
CH.sub.2 Cl.sub.2 (5 ml) N-acylated with cyclopropanecarboxylic
acid chloride (23 .mu.l) in the presence of Et.sub.3 N (50 .mu.l).
After 30 minutes the reaction mixture was washed with 10% Na.sub.2
CO.sub.3 and the organic phase was separated, dried (Na.sub.2
CO.sub.3), filtered and the solvent was evaporated, yielding 55 mg
of an oil.
GC/MS showed M.sup.+ at m/e=303 (1%) and the base peak at m/e-176.
Other prominent peaks appeared at m/e=175 (15%), m/e=129 (45%) and
128 (25%).
The amide (55 mg) was dissolved in dry ether (10 ml) and reduced by
the addition of LiAlH.sub.2 (75 mg). Usual workup gave the raw
product as an oil (29 mg), which was chromatographed (SiO.sub.2 and
eluting with petroleumether:ether (3:1)). The fraction containing
the desired, pure
7-methylthio-2-N-cyclopropylmethyl-N-n-propylamin)tetralin were
pooled and the solvent was evaporated, yielding 14 mg of an
oil.
GC/MS showed M.sup.+ at m/e=289 (35%) and the base peak at m/e=260.
Other prominent peaks appeared at m/e=261 (20%), m/e=324 (10%),
m/e=177 (25%), m/e=176 (10%), m/e=151 (10%), m/e=130 (40%), m/e=129
(45%), m/e=124 (20%) and m/e=84 (15%).
EXAMPLE 26
(+)-R-8-Methoxy-2-(cyclopropylmethylamino)tetralin
(+)-R-8-Methoxy-2-(cyclopropylmethylamino)tetralin (500 mg) was
dissolved in CH.sub.2 Cl.sub.2 (25 ml) and 10% Na.sub.2 CO.sub.3
(25 ml) was added together with acetyl chloride (0.4 g). The
reaction mixture was left stirring for 2 hours. The raw amide
product was extracted to the organic layer, which was dried and
filtered. The organic solvent was removed by evaporation yielding
the amide as an oil. This raw amide was chromatographed SiO.sub.2
and eluting with petroleumether:ether (3.1)). The fractions
containing pure product were pooled and the solvent was evaporated
yielding an oil (324 mg). The amide oil (324 mg) was dissolved in
dry ether (10 ml). To this solution was added LiAlH.sub.2 (300 ml).
Usual workup gave the desired product as an oil (290 mg), which was
chromatographed (SiO.sub.2 and eluting with CH.sub.2 Cl.sub.2 :MeOH
(19.1)). The fractions containing pure product were pooled and the
solvent was evaporated yielding an oil (153 mg).
GC/MS showed M.sup.+ at m/e259.15 (70.9%) and the base peak at
m/e=161.05. Other prominent peaks appeared at m/e=260.15 (14.2%),
m/e=244.15 (32.9%), m/e=218.15 (17.3%), m/e=160.05 (29.7%),
m/e=159.05 (14.9%), and m/e=110.05 (80.4%). The optical rotation
was measured and was found to be .alpha..sub.D.sup.22
=+64.9.degree. (c 1.0, MeOH).
TABLE 1
__________________________________________________________________________
Screening Data on Newly Synthesized Compounds Effects on Dopamine
(DA) and Serotonin (5-HT) Synthesis Rates and on Motor Activity in
Reserpine Pretreated Rats ED50 DOPA.sup.a In vitro binding.sup.a
Bioavailability.sup.f stri hem ED50 5-HTP.sup.b D2 5-HT1A bioch
temp plasma Compound (.mu.mol/kg) limb Motor Act.sup.c
Behavior.sup.d IC50 nM IC50 nM po/sc in
__________________________________________________________________________
% 8-OMe-CPMAT.sup.1 (sc) P(16) I(16) 0.40 + 5-HT syndr 6 12 - -
(po) P(40) I(40) 3.3 + 5-HT syndr 8-OMe-DCPMAT.sup.2 (sc) I(50)
I(50) 1.2 + 5-HT syndr 40000 21 60 36 6-16 (po) I(50) I(50) 2.0 +
5-HT syndr
__________________________________________________________________________
.sup.1 8Methoxy-2-(N-cyclopropylmethyl-N-n-propylamino)tetralin
.sup.2 8Methoxy-2-(N,N-dicyclopropylmethylamino)tetralin .sup.a
Dose giving a half maximal decreases of DOPA formation in the rat
striatal or cortical (NA predominated hemispheres) brain parts. The
value were estimated from doseresponse curves comprising 4 to 6
dose levels (n 4). Maximal decrease was found to be 80% in striatum
and 50% in cortex. Control levels were: striatum 3220 ng/g and
cortex 150 ng/g. .sup.b Dose giving a half maximal decrease of 5HTP
formation in the rat limbic brain part. The values were estimated
from doseresponse curves comprising 4 to 6 levels (n = 4). Maximal
derease was found to be 50%. Control level was: 191 ng/g. "P"
denotes partial agonist, i.e., a submaximal decrease in DOPA or
5HTP formation was noted at the highest dose (shown in brackets in
.mu.mol/kg) tested. .sup.c Motor activity as measured in
photocellequipped motility boxes "+" and "-" denote activation and
no chnage, respectively, as compared to controls (essentially no
locomotion was registered in these controls (reserpinized rats)).
.sup.d The gross behavior of the animals was observed during the
course o the experiments. The 5HT behavioral syndrome consisted of
flat body psoture, abducted hind and forelegs, forepaw treading
(pianoplaying) and Straub tail. .sup.e The affinity of the test
compounds for dopamine D2 receptor sites was determined by
calculating the IC50 value (see text). .sup.f "Bioch" denotes the
bioavailability as estimated by comparing the ED50 values after
s.c. and p.o. administration (reserpinepretreated rats) "Temp"
denotes the bioavailabilty as estimated by comparing the decrease
in rectal temperature after s.c. (25.0 .mu.mol/kg) and p.o. (100.0
.mu.mol/kg) administration of the test drugs in nonpretreated rats
(c.f., FIGS. 1 and 2). "Plasma" denotes the availability as
estimated by comparing plasma drug levels (measured by means of
GC/MS) after s.c. and p.o. administration of test drugs in
nonpretreated rats. ##STR2##
* * * * *